Fibrous tubular conduit for stenting applications

ABSTRACT

A stent composed by a bioabsorbable network of polymer fibers that can be rearranged upon expansion, accommodating for diameter enlargement without the need of a strut or strut pattern and providing temporary support to a biological duct, is provided. Additionally, a stent is provided where the rearranged fibrous network of its expanded state can act as a scaffold for cell infiltration and promote autologous tissue formation.

FIELD OF THE INVENTION

The invention relates to stents and regenerative medicine. Inparticular, the invention relates to fibrous tubular conduits withstenting capacity upon expansion that serve as minimally-invasivelydeliverable scaffolds for cell infiltration and trigger tissueproduction using the patient's own cells.

BACKGROUND OF THE INVENTION

Stents are generally defined as a tubular network of structural elementsusually called struts or bar arms, where expansion is described as amovement of the individual structural elements. Methods to create astrut pattern on tubular structures include laser cutting, die punching,chemical etching, etc. Upon expansion, the stent struts move away fromeach other giving raise to diameter enlargement. Balloon-expandable andself-expanding stents rely on the presence of struts to be deployedminimally-invasively and on the mechanical properties of the basematerial to withstand the forces exerted by the implantation tools andthe host tissue.

Technological advances in the field of regenerative medicine have shownthat fibrous grafts can induce autologous tissue formation. Tubularfibrous structures made out of bioabsorbable polymers can be implantedto act as temporary scaffolds that guide tissue formation. However,grafts with regenerative capacity cannot act as a stent. Due to theirlack of support capability, they require a surgical intervention or mustbe combined with an additional support device such as a stent to beimplanted.

Bioabsorbable polymers with high mechanical properties such as PLA havethe downside of exhibiting brittle fracture. Fibers made out of brittlepolymers exhibit low deformation before they reach their breaking point.Nevertheless, wavy fibers made out of the same material may firststraighten and ultimately stretch and deform, first elastically andlater on plastically. Furthermore, the presence of interconnectionswithin these fibers will result in the possibility of overcoming theseinterconnections upon stretching. A tubular construct made out of aninterconnected network of fibers allows to benefit from the describedmechanisms to achieve expansion of the construct without compromisingits integrity and providing the capacity to fulfill a structuralfunction upon expansion.

The present invention advances the art by overcoming at least some ofthe current shortcomings towards a support device that can be deployed,without the use of a strut pattern, by rearrangement of the fibrousnetwork. Additionally the present invention advances the art byproviding this support device with the capacity to promote autologoustissue formation, acting as a regenerative stent.

SUMMARY OF THE INVENTION

The present invention provides a biocompatible, bioresorbable stent. Thestent is a tubular construct composed of a network of fibers that areable to rearrange to provide diameter enlargement at the implantationsite without relying on a strut pattern. Furthermore, the tubularconstruct in its expanded configuration is able to provide structuralsupport to the host tissue, allowing minimally-invasive anchoring, andserves as a scaffold with regeneration, restoration, growth and/orrepair capabilities, enabling cell infiltration/adhesion/proliferationand new tissue formation if required.

The term “fibrous network” makes reference to an arrangement ofinterconnected fibers, where the fibers take the form of filamentthreads and two types of interconnections can be defined. Fibers can lieadjacent or on top of each other, defined as non-bonded interconnectedfibers. Fibers can be merged while lying adjacent or on top of eachother, defined as physically-bonded interconnected fibers.

The fibrous tubular network is able to act as a stent in the sense thatit can provide structural support to a biological duct afterminimally-invasive implantation, but differs from other stents by notrelying on macroscopic voids, defined by the contours of the stentstruts, to accommodate for diameter expansion, but instead fully relieson rearrangement of its fibrous network.

The stent differs from other vascular grafts as it provides thepossibility of minimally-invasive implantation without requiring anadditional medical device (i.e. complementary stent) to providestructural support to the graft and/or enable anchoring of the graftwithin the host tissue, preventing migration.

The invention is both a stent and a tissue-engineering scaffold at thesame time, defining a fibrous bioresorbable stent with regenerativecapacity, or in short defined as a regenerative stent.

Specifically, a stent is provided for implantation into a biologicalduct. The stent is an expandable tubular construct made out of a fibrousnetwork. The fibrous network distinguishes a first state with a firstdiameter of the tubular conduit determined by a first fiber orientation.The first fiber orientation is characterized by a first fiber dispersionand a first main angle difference, and a first average fiber diameter.The fibrous network further distinguishes a second state with a seconddiameter of the tubular conduit determined by a second fiberorientation. The second fiber orientation is characterized by a secondfiber dispersion and a second main angle difference, and a secondaverage fiber diameter. The first diameter of the tubular conduit issmaller than the second diameter of the tubular conduit.

The transition from the first state to the second state is accommodatedonly by rearrangement of the fibers in the fibrous network and does notrely on a strut pattern. The rearrangement of the fibrous network fromthe first state to the second state is accomplished by: (i) stretchingthe fibers in the fibrous network, (ii) by sliding, breaking, or acombination thereof of the fiber interconnections in the fibrousnetwork, and can be facilitated by acting on the wettability of thefibrous network, or a combination of (i) and (ii).

The fibrous network in the second state provides mechanical support tothe biological duct. The fibrous network in the second state may allowfor cell infiltration and act as a scaffold to induce autologous tissueformation.

In one variation, the first fiber orientation is an arrangement ofrandom fibers, and in this arrangement the first fiber dispersion islarger than the second fiber dispersion.

In another variation, the first fiber orientation is an arrangement ofcontrolled fibers and in this arrangement the first main angledifference is equal or larger than the second main angle difference.

In yet another variation, the first fiber diameter is equal to or largerthan the second fiber diameter.

In still another variation, the rearrangement of the fibrous network canbe facilitated by acting on the wettability of the fibrous network toaccommodate the transition from state 1 to state 2.

In still another variation, the tubular construct can be composed of oneor more layers.

In still another variation, the tubular construct is shaped to inducechanges in geometry or openings.

In another embodiment, the invention pertains to a method formanufacturing a stent with bio-absorbable fibers including the steps ofproviding a tubular mold, defining a fibrous polymer network on themold, and separating the material from the mold. The fibrous network canbe, but is not necessarily, produced by electrospinning.

In yet another embodiment, the invention pertains to a method ofmanufacturing a valved-stent including the steps of providing a leafletstructure to the stent (either by suturing the leaflets, shaping ordefining leaflets by a less dense fibrous network that can be bentinwards).

In still another embodiment, the invention pertains to a method forminimally-invasive relief of obstructive disease, including identifyingan obstructed blood vessel or other tubular conduit in need, andinserting a tubular construct into said vessel or conduit. Thecomposition can, but not necessarily, allow for new tissue formation.

In still another embodiment, the invention pertains to a method forminimally-invasive delivery of tissue-engineering scaffolds for bloodvessels, including identifying a blood vessel in need of tissue repairor engineering, and inserting the tubular construct into the bloodvessel. The new passage for blood is engineered inside the nativeartery.

In still another embodiment, the invention pertains to a method ofminimally-invasive treatment of a patient with a cardiovascular disease,including identifying a blood vessel in a patient in need of obstructionrelief or tissue engineering, and inserting the a tubular construct intothe blood vessel.

In still another embodiment, the invention pertains to a method ofminimally-invasive treatment of aneurysmatic arteries, includingidentifying a blood vessel with an aneurysm, and inserting a tubularconstruct into the blood vessel. The new passage for blood is engineeredwithin the native artery

In still another embodiment, the invention pertains to a method ofminimally-invasive treatment of congenital heart disease in growingpatients, including identifying a blood vessel in said patients, andinserting a tubular construct into the blood vessel. The new passage forblood is engineered within the native artery and does not hamper somaticgrowth.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C show according to an exemplary embodiment of the inventionimplantation of the construct inside an obstructed vessel (FIG. 1A), theconstruct expands, fibers reorganize and cells from the blood infiltratethe fibrous mesh (FIG. 1B), where cells synthesize new tissue while thefibers safely dissolve over time where after a newly formed vesselremains (FIG. 1C).

FIG. 2 shows according to an exemplary embodiment of the inventiondefining the orientation of the construct respectively to the fibers(FIG. 2).

FIGS. 3A-B show according to an exemplary embodiment of the invention anexample how constructs can be created using electrospinning, and howrandom (FIG. 3A) and controlled (FIG. 3B) fiber orientations could beobtained.

FIGS. 4A-B show according to an exemplary embodiment of the inventionhow the fibers will reorganize in a random fiber orientation scenariofor a construct going from state 1 to an enlarged diameter in state 2(FIG. 4A), and how the fibers will reorganize in a controlled fiberorientation scenario for a construct going from state 1 to an enlargeddiameter in state 2 (FIG. 4B).

FIGS. 5A-B show according to an exemplary embodiment of the inventionafter image analysis on the microscopically obtained images, how themain angle and dispersion of the constructs alter when going from state1 to state 2 in a random fiber orientation scenario. Here the mainparameter of interest is the realignment index, I_(σ) (FIG. 5A). In caseof the controlled fiber orientation scenario, two clear peaks can beidentified after image analyses processing, where in this case the mainparameter of interest is the reorientation index, I_(Δα) (FIG. 5B).

FIG. 6 shows according to an exemplary embodiment of the invention therange of the realignment (I_(σ)) and reorientation (□_(Aα)) index, whichwould be applicable for making the transition from state 1 to state 2(FIG. 6).

FIGS. 7A-F show according to an exemplary embodiment of the inventionwhere a fibrous construct has been produced and expanded in diameter totransit from state 1 to state 2 (FIG. 7A). In this case the diameter hasbeen enlarged to go from 1299 μm in state 1 to 4099 μm in state 2 (FIG.7B). Microscopic pictures of the fibers were made by using scanningelectron microscopy, when the construct being in state 1 and state 2(FIG. 7C-D). The images were analyzed using image analyses software(Fiji, ImageJ), which determined a value for σ₁=26.24° and value forσ₂=14.00° (FIG. 7E-F). This results in a realignment index ofI_(σ)=0.53, confirming the fiber reorganization.

FIG. 8 shows according to an exemplary embodiment of the invention howsimultaneous diameter enlargement and load bearing capacity can besimultaneously obtained after transition to state 2 for a PLA-basedelectrospun scaffold immersed in an ethanol solution to enhancestretchability and evaluation of the crush force after subsequentevaporation of the alcohol.

FIGS. 9A-D show according to an exemplary embodiment of the inventionhow different aqueous alcohol solutions (FIGS. 9A-D) in contact with thePLA based solid surface affects the wettability of the polymer surface.The contact angle of alcohol droplets on the PLA surface was calculatedto determine the wettability. Pure water without alcohol had a contactangle of 85°, by mixing water with 25% methanol the contact angledropped to 60°, with 25% ethanol to 45° and with 25% 1-propanol to 20°.Here, a method of using longer chain alcohols is used to increase thestretchability of PLA constructs in a laboratory setting.

FIG. 10 shows according to an exemplary embodiment of the invention theeffects of adjusted wettability properties of the polymer fiber surfaceon the mechanical properties of PLA based fibrous conduits, usingdifferent alcohols. Including methanol resulted in an increase ofelongation at break 2.5 times compared to pure water whereas ethanolrepresented an increase of 3.67 times and 1-propanol even prevented ringrupture. This confirms that increasing the wettability of the polymerfiber surface comprising the fibrous network, is translated in anincrease of the elongation at break.

FIG. 11 shows according to an exemplary embodiment of the invention theeffects of temporary adjusting the wettability of the fiber surfacecomprising the fibrous network using alcohol such as ethanol, on themechanical properties of a PLA-based fibrous tubular conduits. Testswere performed on: i) dry electrospun rings, ii) rings immersed in purewater, iii) rings immersed in a 25% ethanol solution and iii) ringsimmersed in a 25% ethanol solution where after ethanol was depleted bymultiple washing steps in water. This shows that ethanol has a temporaryeffect where after depletion, mechanical properties almost fullyrecovered.

FIG. 12 shows according to an exemplary embodiment of the invention theeffect of strain rate on the mechanical properties of PLA-based fibroustubular conduits emerged in pure water. Lowering strain rates improvesthe fibers to reorganize enhancing the stretch capacity of theconstruct.

FIG. 13 shows in Example A a conventional concept of stent expansionbased on a strut pattern. Out of a solid wall tube, a strut pattern isembedded to make the structure act as a stent. Expansion from state 1 tostate 2 is enabled by the geometrical adjustment of the strut pattern,where the established open voids become larger. Example B, according toan exemplary embodiment of the invention, shows the concept of usingfiber reorganization to allow for stent expansion. Expansion from state1 to state 2 is solely enabled by reorganization of the fibers in thefibrous network, hence not relying on a strut pattern. Structuralsupport in state 2 is shown by maintained diameter enlargement achievedin the silicon-mocking vessel.

FIGS. 14A-F show according to an exemplary embodiment of the inventionin FIG. 14A the device being inserted using a minimally-invasiveapproach mounted on a balloon catheter. FIG. 14B shows the deviceundergoing the transition from state 1 to state 2 upon stent deployment,by which the device is anchored into the artery. FIG. 14C shows, afterremoval of the balloon catheter, that the device maintains mechanicalsupport to keep the stenotic area open. FIG. 14D shows a magnificationof the wall of the construct, to reveal the porous structure beingentirely composed of layers of stacked fibers composing a fibrousnetwork. FIG. 14E shows, the ability for host cells to infiltrate theporous mesh. In the example, cells from the bloodstream simultaneouslyadhere to the fibers inside the as well as to the fibers on the luminalside simultaneously. FIG. 14F shows the fibrous network being resorbedby the body, as the cells synthesize new tissue filling up the voidsinside the fibrous mesh.

FIG. 15 shows according to an exemplary embodiment of the invention asliding non-bonded interconnection (i) initially located at referencepoint 1 and relocated upon expansion of the construct FIG. 16 showsaccording to an exemplary embodiment of the invention complete break ofinterconnection i of physically-bonded fibers, leaving individual fibers1 and 2 intact.

FIG. 17 shows according to an exemplary embodiment of the inventionpartial break of interconnection i of physically bonded fibers 1 and 2,disrupting one of the fibers, i.e. fiber 1.

FIGS. 18A-C show according to an exemplary embodiment of the invention aregenerative stent implanted inside the abdominal aorta of a rat FIG.18A, providing in-vivo evidence of minimally-invasive implantation ofregenerative stents in an animal model. FIG. 18A also shows that thestent provides structural support to the artery after implantation bydisplaying a patent and opened artery. FIG. 18B shows histology on theexplant of the embodiment two weeks after implantation in the abdominalaorta of a rat. Cells are present in both the native artery as well ason the stent. Uniform infiltration of host derived cells is marked bythe highlighted dots representing individual cells. In FIG. 18C ahistology picture shows a section of the stent inside the abdominalaorta of a rat. The native artery is shown on the top right, where theembodiment is on the bottom left. Signs of new tissue formationthroughout the stent, already two weeks after implantation, is evidencedby the presence of dark stained tissue components.

FIG. 19 shows according to an exemplary embodiment of the inventiondifferent types of clinically relevant vascular applications whereregenerative stents can be used.

FIGS. 20A-E show according to an exemplary embodiment of the invention amethod to produce a valved-stent. The valved-stent has a fibrous polymertubular conduit (1), of thickness T1 and length L1 that acts as a stent(FIG. 20A) and a fibrous polymer tube (2) of thickness T2 and length L1that acts as a valve scaffold (FIG. 20B). The valve scaffold can beplaced inside or outside the stent (FIG. 20C). The valve scaffold isflipped inwards to create the valve inside the stent (FIG. 20D).Constraints, such as bioabsorbable sutures, or inserts can be placed onthe scaffold, defining the leaflets of the valve (FIG. 20E). In thiscase, a tri-leaflet valved-stent is created.

FIGS. 21A-D show according to an exemplary embodiment of the inventionfibrous conduits can be positioned in front of a bifurcation or otheropening after implantation.

DETAILED DESCRIPTION

The term “tubular” pertains to an approximate shape of a cylinder andcan include conical shapes or other variations such as curvatures, sidebranches, bifurcations, sinuses, ovality, concave and convex shapedsegments.

The term “biological duct” refers to a part of the circulatory systemincluding cardiovascular system (pulmonary and systemic circulation,i.e. vasculature related to the heart such as the coronary vessels aswell as the peripheral vasculature), neurovascular system, and lymphaticsystem, related to arteries, veins and capillaries, part of thedigestive system (including the gastrointestinal tract), part of theurinary system, or any related organ thereof, or any other part of abiological system where a duct can be defined and the duct is suitableto receive the stent according to embodiments of the present invention.

The term “structural support” refers to the capacity to open abiological duct causing an increase in diameter or maintaining theoriginal diameter of the biological duct after recoil, preventingcollapse and or maintaining patency. One way to evaluate the structuralsupport capacity is to determine the force after vertical or radialcompression.

The term “scaffold” refers to a structure that enables to infiltrate,attach and/or grow cells and/or tissue.

The term “stent” refers to a structure that provides structural supportto the biological duct upon self-expansion or balloon expansion.

The term “construct” refers to a tubular shape that can act as scaffoldor a stent. For example, a scaffold can be defined as a construct thatdoes not necessarily provide structural support.

The term “regenerative stent” refers to a tubular fibrous construct thatacts as a scaffold and a stent simultaneously.

This invention describes a tubular construct, composed of abioabsorbable fibrous network having layers of interconnected fibers.The construct can be minimally-invasively delivered into a biologicalduct. Once at the intervention location (FIG. 1A), the construct willundergo the transition from state 1 (FIG. 14A) to state 2 (FIG. 14B),inducing fibers to enhance rearrangement towards the circumferentialdirection (FIG. 2) upon expansion, enabling diameter enlargement of theconstruct. The construct can provide structural support to thebiological duct in state 2 acting as a stent that does not rely on astrut pattern to enable expansion (FIG. 14C). Because of its fibrousnature, in pores are defined within the structure (FIG. 14D) and cellsfrom the blood and adjacent tissue can infiltrate the construct (FIGS.1B & 14E). The infiltrated cells can synthesize new tissue (FIG. 14F).Over time, the fibrous network can safely dissolve inside the body. Thiswill eventually result in reconstructed tissue (FIG. 1C). The additionalbenefit for cardiovascular applications is that, due to the consistentporous structure, a gradual and uniform degradation of the construct canbe expected and endothelialization will be eased, reducing the risk ofinflammation and thrombus formation. Furthermore, due to the lack of astrut pattern in the stent profile, severe turbulent flow is expected tobe prevented.

By combining the advantages of a fully biodegradable stent composed of afibrous network, together with the advantages of a regenerativescaffold, this device could allow for: minimally-invasive delivery,large expansion ratios, structural support upon inflation, temporarysupport, enhanced resorption, internal leakage prevention, full lesioncoverage, cell infiltration, natural tissue formation, constructforeshortening prevention, uniform endothelialization, turbulent flowprevention, low profile constructs, enhanced flexibility, diseaseregression, restored functionality of the biological duct and naturalgrowth of the biological duct or a combination thereof.

In some embodiments, diameter enlargement will promote circumferentialalignment of the fibers. This will enhance the load bearing capacity ofthe stent and benefit native-like tissue formation. Cells can alignalong the fibers of the construct and produce tissue component such ascollagen in the same direction, resembling the native configuration.

In some embodiments rearrangement of the fibrous network could lead tofiber stretch. Hereby the fibers can be elongated without resulting in abrittle behavior that causes failure of the construct upon expansion.Fiber stretch could benefit the local mechanical fiber properties on amolecular level by aligning the polymer chains, which might result in astiffening effect of the fiber.

Method of Making

In an exemplary embodiment, fibrous tubular conduits could be producedby using electrospinning technology. A biodegradable polymer can bedissolved in a solvent to obtain a polymer solution. This solution couldcontain either a single polymer or multiple polymers into a blend. Thepolymer solution is guided towards the nozzle of the electrospinningequipment. A rotating mandrel is positioned in front of the nozzle at aset distance. A voltage difference is applied over the nozzle and themandrel, by which a taylor cone is formed in front of the nozzle. Fromthis taylor cone, a continuous polymer jet is ejected towards themandrel. Since the mandrel is rotating, the polymer fiber is wrappedaround the target. By moving the nozzle back and forward over the lengthof the target, the length of the electrospun scaffold can be defined(FIG. 3A).

To control the orientation of the fibers on the target, from a randomtowards an aligned configuration, electrospinning settings can beadjusted. There are multiple possible parameter combinations to reachthis state. One example is to increase the rotation speed of themandrel, by which fibers will be more circumferentially aligned on thetarget (FIG. 3B). To control the angle of the fibers relative to thesymmetry axes of the target, the travel speed of the nozzle can beadjusted while spinning aligned fibers. By defining the rotational speedof the mandrel, the appropriate travel speed of the nozzle can becalculated, to reach a controlled fiber angle. The travel speed, both inforward and backward direction, can be set separately in order to createone or multiple main fiber angles. When preferred, multiple nozzles canspin on the same target under different conditions to simultaneously usemultiple polymer materials. Also both random and aligned fibers could bespun simultaneously onto one target by changing individual conditionsfrom multiple nozzles. By setting the spinning time, the wall thicknessof the scaffold can be controlled. Electrospinning settings, thecomposition of the solvent as well as the concentration of the polymersolution can be adjusted to control fiber diameter and pore size.

Other production methods to produce similar fibrous constructs could be,emulsion electrospinning, coaxial electrospinning, melt electrospinning,electrostatic drawing, braiding, weaving, knitting, additivemanufacturing, 3D printing, bioprinting, electro spraying, polymerjetting, injection molding, casting or any other fiber production methodor a combination thereof.

After manufacturing, the fibrous network might require an annealingstep. Annealing is a heat treatment that can alter the physical and orchemical properties of a material. In some cases the fibrous networkwill be heated above the Tg. The annealing temperature will bemaintained for a defined period of time followed by a cooling phase.Annealing can be performed in several steps, each step can have variousrepetitions and durations between cycles and between repetitions.

The optimum material to manufacture the construct depends on thebiological duct where it will be inserted and the nature of the diseaseto be treated. Biocompatible materials can include:

-   -   bioresorbable polymers (such as poly lactic acid (PLA),        including poly(L-lactide), poly(D-lactide), poly(D,L-lactide),        as well as polyglycolid acid (PGA), polycaprolactone,        polydioxanone, poly(trimethylene carbonate),        poly(4-hydroxybutyrate), poly(ester amides) (PEA),        polyurethanes, poly(trimethylene carbonate), poly(ethylene        glycol), poly(vinyl alcohol), polyvinylpyrrolidone, and        copolymers thereof),    -   non bioresorbable materials (such as polypropylene,        polyethylene, polyethylene terephthalate,        polytetrafluoroethylene, polyaryletherketone, nylon, fluorinated        ethylene propylene, polybutester, and silicone, or copolymers        thereof),    -   biological components (such as hyaluronan, collagen, gelatin,        chitosan, alginate, aloe/pectin, cellulose or other biological        materials originating from tissues from either autologous,        allergenic or xenogenic origin),    -   or a combination thereof.

The polymers can be of the D-iso form, the L-isoform, or a mixture ofboth. Multiple polymers and copolymers can be mixed and blended intodifferent ratios. The polymer fibers can be crosslinked. Someembodiments may include supramolecular chemistry includingsupramolecular polymers, linking mechanisms or moieties. Someembodiments may comprise shape-memory polymers.

In some embodiments multiple fibrous layers with different densities canbe combined. Cell infiltration, and hence tissue formation, can beprevented or enabled by adjusting the porosity of a fibrous layer.Adjusting fiber spacing and/or fiber diameter and layer thickness canalter the conditions for cell infiltration. In this way cellinfiltration and migration can be controlled with dense structuredlayers, which face either the outer and/or luminal side of theconstruct.

Impermeable layers can be added based on either densely packed fibers,porous structures with high surface tension or non-porous networks, toprevent fluid leakage; for purposes where for instance lesions or ductsneed to be closed.

In some embodiments, speed of bioresorption can be tuned by acting onthe molecular weight of the polymer, combining polymers with differentintrinsic bioresorption speed and/or modifying the porosity of thefibrous network, the fiber diameter and/or the number of layers ofstacked fibers.

Method of Testing/Evaluating

To evaluate the fiber distribution and orientation of the fibers fromthe fibrous network, microscopic images can be obtained for instance byusing scanning electron microscopy. After obtaining the macroscopicpicture, image analyses software can be used to calculate the obtainedfiber distribution and orientation. One example of a free image analysissoftware is Fiji (ImageJ). By using the directionality plugin, the fiberorientation and distribution is calculated by either using Fouriercomponents or by calculating a local gradient orientation to analyze theimage. The software will fit a mathematical distribution to the data,which in the standard configuration is a Gaussian distribution. In thisway, both fiber dispersion (σ) as well as the main fiber angle (α) canbe obtained, where the fiber angle is the center, and the dispersion thestandard deviation of the Gaussian fit.

To enable minimally-invasive implantation and anchoring of theconstruct, the diameter needs to be enlarged once it is positioned atthe desired location inside the biological duct. Diameter enlargement ofthe construct is facilitated by making use of fiber reorganization ofthe fibrous network from which the construct is composed of.

To discriminate between the initial and expanded states, we define state1 as being the construct after production, and state 2 as being the sameconstruct after diameter enlargement. The construct can act as a stentwhen reaching state 2. In order to enable diameter enlargement, fiberreorganization between state 1 and state 2 has to be induced. Thefibrous network of the construct in state 1 could have a random fiberorganization (Scenario A) or a controlled fiber organization (ScenarioB), or a combination there of.

Scenario A: Random Fiber Orientation

State 1: is defined as a scaffold having fibers randomly oriented (FIG.4A). The directionality histogram describes a broad peak area withseveral maximums of high intensity defining a rather flat Gaussianfitting curve (FIG. 5A). This is captured by a relatively high value offiber dispersion σ. In this case, the fiber angle α merely describes thecenter of the Gaussian curve with no real physical relevance.

State 2: the diameter of the scaffold from state 1 has been enlargedresulting in state 2, which causes realignment of the fibers (FIG. 4A).The directionality histogram describes a narrowed peak area surroundingone preferred orientation (FIG. 5A). This is captured by a lowered valueof σ and a value of α, which approaches 90 degrees, here defined as thecircumferential direction (FIG. 2).

The relevant parameter here is σ. To prove fiber alignment, the degreeof fiber dispersion is quantified by comparing σ from state 1 (σ₁) withσ from state 2 (σ₂), resulting in a realignment index, which is definedas I_(σ)=σ₂ divided by σ₁, and can describe any range between noalignment (I_(σ)=1) or complete alignment (I_(σ)=0). Any I_(σ)<1confirms that fiber reorganization is induced to enable the transitionfrom state 1 to state 2 (FIG. 6).

For the sake of clarity, even a small degree of realignment is crucialbecause it enables diameter expansion without the need of a strutpattern, unlike conventional stents that usually relay on macroscopicvoids to enable expansion. Here, lower values of the realignment indexare expected to have favored mechanical properties.

Scenario B: Controlled Fiber Orientation

State 1: is defined as a scaffold having fibers distributed in one ormore main orientations. The directionality histogram in this exampledescribes two main orientations by two narrow peaks defining the mainangles α₁ and α₂. The fiber dispersions σ₁ and σ₂ are low (in agreementwith the high degree of fiber alignment in both directions).

State 2: the diameter of the scaffold from state 1 has been enlarged toresult in state 2, which causes reorientation of the fibers. Thedirectionality histogram describes two narrow peaks, which have becomecloser to 90 degrees describing circumferential alignment. Clearly therelevant parameter here is α. However the main angle difference (Δα)describes the existence of two families of fibers and the reduction ofAu between states describes the alignment. The reorientation index isdefined as I_(Δα)=Δα₂ divided by Δα₁, and can describe any range betweenno reorientation (I_(Δα)=1) or complete reorientation (I_(Δα)=0). AnyI_(Δα)<1 confirms that fiber reorientation is induced to enable thetransition from state 1 to state 2 (FIG. 6).

The construct can be balloon expandable. Here a tubular construct can beproduced to meet state 1. The construct is mounted over the balloon of aballoon catheter. The construct might be annealed over the balloon tofacilitate proper fixation of the construct. Upon implantation, theballoon will be inflated and the construct will be deployed into thebiological duct. Upon deflation of the balloon, the construct will reachstate 2.

The construct can be self-expandable. Here a construct can be producedin a larger diameter and be crimped to reached state 1. The stent isloaded into a shielded catheter device. Upon implantation the shieldwill be removed and the stent will be deployed into the biological ductto reach state 2.

In one of the embodiments of the invention, the fibers will be exposedto a circumferential stress upon expansion. Fibers will be stretchedcircumferentially and interconnections will be overcome resulting indiameter enlargement of the structure without exhibiting a brittlebehavior. In this way, the fibrous network has rearranged to enablediameter enlargement. In state 2, the enlarged construct will supportthe load of the biological duct where it has been implanted to act as astent, which will be enabled by a suitable selection of the material andthe mechanical properties that prevent collapse of the structure.

Comparison

Fibers in current stents in the art, are not or will not be reorientedand/or realigned, stretched and/or straightened upon enlargement ofstent diameter. Those fibers could possibly change orientation due torotation by opening of the strut pattern. However, in case those fiberswere randomly oriented in state 1, they would remain random in state 2.This makes I_(σ)=1. Furthermore, in case those fibers were controlledoriented (aligned in circumferential direction) in state 1, they wouldbecome less circumferentially aligned in state 2. In that case I_(Δα)>1.

Overcoming the Interconnections

As described supra, fibrous tubular conduits can be implantedminimally-invasively to support biological ducts. Upon expansion, fiberreorganization is essential to achieve diameter enlargement withoutcompromising the integrity of the construct, where after the reorientedfibers need to guarantee proper anchoring of the construct and patencyof the biological duct. For this purpose, not only the mechanicalbehavior of the single fiber needs to be considered, but also theinteraction between fibers.

Fibers, held together by fiber interconnections, can form a tubularconstruct. Fibers can lie adjacent or on top of each other, which isdefined as non-bonded interconnected fibers. Fibers can be merged whilelying adjacent or on top of each other, which is defined asphysically-bonded interconnected fibers. To ease fiber rearrangementupon diameter enlargement, fiber interconnections can be overcome.Overcoming fiber interconnections during diameter enlargement couldenhance fiber mobility allowing them to straighten, reorient, elongateand/or slide; improving the stretchability of the tubular construct.

The term “overcoming the interconnections” in this application means:

-   -   a) Sliding of non-bonded fibers, where the interconnection will        be relocated. As shown in FIG. 15, two fibers are initially        interconnected at point (1) where the interconnection is        indicated by a circle (i). Initially (1) and (i) are coincident.        As stretch is applied to the fibrous network, the        interconnection (i) slides to a different location, differing in        position with respect to point (1).    -   b) Breaking of the interconnection of bonded fibers, where the        bonded interconnection can be seen as predefined breaking point.        In this case stress will be accumulated at the interconnection        which will eventually break:        -   b1) completely: leaving both fibers intact. As shown in FIG.            16, two fibers (1) and (2) are bonded at the interconnection            (i). As stretch is applied to the fibrous network, the            interconnection disappears and the fibers become            independent;        -   b2) partially: segmenting one of the fibers. As shown in            FIG. 17 two fibers (1) and (2) are bonded at the            interconnection (i). As stretch is applied to the fibrous            network, the interconnection is disrupted and fiber (1) has            been separated in two fragments.

Relocating the interconnections could be essential to secure mechanicalintegrity of the expanded fibrous graft.

Wettability

Wettability is an important factor that can affect the rearrangementcapacity of the fibrous network in an aqueous environment. Tuning thewettability of the fibrous network can affect the mechanical propertiesand biological interactions, and the degradation speed of the fibers aswell as the interconnections, by which rearrangement of the fibrousnetwork can be eased. The wettability of the fibrous structure has to betuned in such a way that it allows for rearrangement of the fibersresiding in the fibrous network upon diameter enlargement, but inaddition needs to allow the rearranged fibrous network to maintain themechanical load applied by the biological duct.

On the level of the fibers, tuning the wettability could influence (butis not limited to);

-   -   the capacity of water to penetrate into the polymer and hence        could influence:        -   the Tg and Tm of a (co)polymer by which the mechanical            characteristics may be altered.        -   the degradation speed of the polymer caused by bulk            hydrolysis    -   the capacity of biological substances (such as but not limited        to cells, proteins and enzymes) to adhere to the fiber or        limit/prevent adhesion to act as a non-fouling surface;    -   the degradation speed of the polymer caused by surface        hydrolysis.

On the level of the fiber interconnections, tuning the wettability couldinfluence (but is not limited to):

-   -   the sliding capacity of non-physically bonded fibers by which        friction between the fibers will be altered to act as a        lubricant and favors the mobility of individual fibers    -   the sliding capacity of non-physically bonded fibers caused by        attractive forces between hydrophobic surfaces.    -   the capacity of water to infiltrate into the fiber        interconnections, hence could act as a plasticizer/solvent by        which the physically bonded fibers could be overcome.

Relocation of non-bonded interconnections or creation of newphysically-bonded interconnections, either prior, upon or postimplantation, could be beneficial to improve mechanical support and forshaping purposes to include for instance sinuses, convex/concave shapes,curvature and/or, shaping voids to enable access to side branches, etc.In addition, this would be an attractive method to pre-shape other typesof fibrous structures such as heart valve geometries. Shaping mightrequire additional constraints to induce the desired geometry and mightrequire additional annealing steps. Relocation or creation of newinterconnection can be achieved by several means but not limited to,thermal treatment, chemical treatment, photo- or ultrasound activation,etc., either in-vivo or ex-vivo.

This invention further describes methods to tune the wettability of thefibrous network and facilitate fiber rearrangement.

Methods to Facilitate Rearrangement of the Fibrous Network

Surface Treatment

The fibrous network can undergo a high-energy surface treatment such asplasma, ultra-violet or radiation to cause modifications on a chemicaland physical level on the polymer surfaces. This increases surfacewettability when exposed to an aqueous environment. This will easerearrangement of the fibrous network.

Surface Coating

Besides surface treatment, coating the fibers with a hydrophilicmaterial can also increase wettability when exposed to an aqueousenvironment. It should be taken into account that applying a coatingcould greatly affect the mechanical integrity of the fibrous conduit,where coatings could act as lubricants or gluing agents when beingapplied to fibrous graft applications.

Increasing Temperature

The temperature of the environment at which diameter enlargement of thefibrous conduit takes place also affects wettability of the aqueoussolution on a polymer fiber surface, where higher temperatures willimprove this effect. The aqueous solution could either be water orblood, mixed with or without an alcohol. The effect of temperature onthe wettability has a higher influence on low alcohol concentrations andshort chain alcohols, compared to high alcohol concentrations and longchain alcohols. Temporarily enhancing the temperature at the side ofimplantation could therefore ease rearrangement of the fibrous network.

Alcohol as an Additive to the Aqueous Solution

Alcohols are good additives to increase the wettability of hydrophobicpolymer surfaces in an aqueous solution. Longer alcohol chains couldprogressively enhance this effect by either lowering the surface tensionof the aqueous solution and/or binding of the alcohol molecules to theimperfections of the fibers. In other words, by adding alcohol to anaqueous solution, a solvent film will be formed over the surfaces of thefibers that will enhance the mobility of fibers, easing fiberrearrangement and facilitating diameter enlargement of the conduit. Whenthe preferred diameter has been reached, the medium could be replaced ordepleted from the alcohol to reverse this effect.

The use of alcohols such as ethanol could also have a swelling effect atthe surface of several polymers; thereby breaking the junctions ofbonded fibers, before or during strain application. This could improvefiber mobility and ease rearrangement of the fibrous network allowingthem to slide over one another, and should be translated in aconsiderable increase in stretchability of the construct. After removalof alcohol from the aqueous solution, swelling will be reversed andcould restore bonding of the fibers, caused by evaporation of thesolvent and concomitant adhesion and interaction between the solvatedpolymer chains at the site of anchoring. In this way, the stretchabilityof the fibrous conduit could be temporarily increased during diameterenlargement and the structural support could be restored after removalof alcohol from the medium.

In addition, the use of alcohol could have a plasticizing effect on thematerial via influencing the glass transition temperature (Tg) and/orthe melting temperature (Tm) and respective melting enthalpy (ΔHm). Thiscould enhance the flexibility of the fibers and contribute to make theconstruct more stretchable.

Alcohol could be incorporated inside the fibrous tubular constructs byimmersing the graft in an aqueous alcohol solution, or by incorporatingan alcohol gel within the structure. Such a gel could be produced byspinning separate fibers from poly(ethylene glycol) (PEG) based polymers(which have the ability to form a hydrogel), in addition to the basematerial fibers (i.e PLA) and immersing the construct in an aqueousalcohol solution to form the gel prior to implantation. The benefit ofthe alcohol gel is that it will remain stable within the constructduring implantation for a certain period of time, promotingstretchability of the structure to allow for diameter enlargement. Atthe final diameter and by dissolution of the gel, the structure willrecover its load bearing function.

Adjusting the Polymer Composition

Rearrangement of the fibrous network can be eased by acting on thepolymer composition. Including components with different mechanicalproperties (such as elongation at break or elastic modulus) can enhancethe stretching behavior.

In addition, blending or mixing polymers or creating a copolymer withcomponents of different hydrophobic or hydrophilic characteristics canbe incorporated to modify the wettability of the fibers, easing fiberrearrangement without compromising the structural capabilities of theconstruct. This method is more consistent with an in-vivo scenario wherethe addition of alcohol upon expansion would be less preferred.

Other methods to ease the rearrangement of the fibrous network withoutaffecting the wettability of the fibrous network is to lower the strainrate during diameter enlargement of the conduit during implantation.Lowering strain rates will ease the rearrangement of the fibrous network

Methods of Testing/Evaluating

The degree of wetting can be measured by analyzing the contact angle (Θ)of a liquid droplet on a solid surface. A high contact angle means thatthe surface is hydrophobic. A low contact angle means that the surfaceis hydrophilic, indicating good wettability of the surface with respectto the liquid. By placing a liquid droplet on a solid surface, Θ can bevisualized by microscopy and quantified by imaging. An improvement instretchability can be assessed using mechanical analyses such asuniaxial tensile testing. Improved stretchability is expected to resultin an enhanced elongation at break and a decrease in the force that isrequired to elongate the fibrous structures. In addition, a suitableperformance and functionality of the construct can be evaluated byimplantation in an animal model and subsequent follow-up, where theconstruct must prove to be competent as a stent that can be deliveredminimally-invasively and as a scaffold that can induce tissue formation,hence as act a regenerative stent.

Example 1

A 2 mm electrospun PLA-based tubular graft was immersed in an ethanolsolution and subsequently expanded with a balloon, duplicating itsdiameter. The tube was dried evaporating the alcohol and the structureshowed a load bearing capacity comparable to metal stent alternatives ofsimilar dimensions reported in literature (FIG. 8)

Example 2

To assess the influence of alcohols on the wettability of PLA in aqueousenvironment, solutions including alcohols with increasing chain lengthwhere prepared and the resulting contact angles formed over a solid PLAsurface were compared to pure water. The addition of pure water on thePLA substrate resulted in a contact angle of 85° (FIG. 9A) that lowersto 60° after including 25% of methanol (FIG. 9B), to 45° with 25% ofethanol (FIG. 9C) and to 20° with 25% of 1-propanol (FIG. 9D).

Example 3

The effect of alcohol on the stretchability of PLA based fibrous tubularconduits was evaluated by uniaxial tensile testing at room temperature.Rings of 0.5 mm width were obtained from 20 mm electrospun PLA tubesafter 1 hour spinning. Samples were immersed in pure water and in 25%solutions of the alcohol of interest and tested at a strain rate of 2.33mm/s. Adding methanol resulted in an increase of elongation at break 2.5times compared to pure water whereas ethanol represented an increase of3.67 times and 1-propanol even prevented ring rupture (FIG. 10).

Example 4

The effect of alcohol on the mechanical properties of PLA-based fibroustubular conduits after alcohol depletion was investigated using uniaxialtensile testing at room temperature. Tests were performed on: i) dryelectrospun rings, ii) rings immersed in pure water, iii) rings immersedin a 25% ethanol solution and iii) rings immersed in a 25% ethanolsolution where after ethanol was depleted by multiple washing steps inwater. This example shows that ethanol has an effect on the mechanicalproperties of PLA-based fibrous tubular conduits, which is to a certainextent reversible (FIG. 11). Testing dry PLA-based rings puts inevidence the advantage of the electrospinning technique for thestretchability. Compared to the elongation at break of bulk PLA,electrospun PLA presents an increase of two orders of magnitude. Forcesdecreased when samples were immersed in water and even presented a moreconsiderable decrease when immersed in an ethanol solution. Afterdepletion of ethanol, forces are restored to values that are comparableto water immersion.

Example 5

Strain rate plays an important role in the mechanical behavior ofPLA-based scaffolds. Uniaxial tensile tests of PLA-based rings wererepeated decreasing the stretching speed to 0.023 mm/s (FIG. 12).Lowering strain rates may allow the fibers to reorganize and relaximproving the stretch capacity of the construct.

Example 6

A regenerative stent, were the stretchability of the construct has beenenhanced by addition of alcohol to the aqueous solution where theconstruct was expanded (FIG. 7A). The construct can transition fromstate 1 to state 2 without compromising its integrity upon expansion(FIG. 7A). The diameter enlargement achieved upon balloon inflation isdepicted in FIG. 7B. The fiber dispersion and histograms correspondingto both states are depicted in FIGS. 7 C, D, E & F.

Example 7

A regenerative stent, were the stretchability of the construct has beenenhanced by acting on the polymer composition has beenminimally-invasively delivered in the abdominal aorta of a rat byballoon expansion (FIGS. 18A-C). This example illustrates a method totreat vascular diseases with one embodiment of our invention. The stenthas been successfully deployed in the native artery byminimally-invasive methods (FIG. 18A). Furthermore, cells are able toinfiltrate the construct and start producing tissue already two weeksafter implantation (FIGS. 18 B-C). The regenerative stent has beenexpanded without relying on a strut pattern and has maintained itssupportive capacity without compromising its integrity afterimplantation.

Methods of Using

Various clinical indications could highly benefit from regenerativestents and bioabsorbable stents that do not present a strut pattern(FIG. 19). Each particular indication has distinctive features andrequirements to be taken into account which, for the sake of clarity,should be evaluated case by case, further elucidate in some examples.

Example 1

Atherosclerosis is a disease that develops due to a deposit of fattymaterials such as cholesterol in the arteries causing hardening of thevascular wall and narrowing of the artery. It is believed that thetrigger and progression of atherosclerosis is related to inflammatoryprocesses in the endothelial cells and/or smooth muscle cells of thevessel wall associated with retained low density lipid (LDL) particles.Current hypothesis suggest that a covering thin-cap fibroatheroma willinduce plaque regression and formation of a thick shield of coveringtissue. As regenerative stents will initiate the formation of a tissuelayer on top of the fibrous cap, it could facilitate plaque regression.

Example 2

Aneurysms are locally weakened areas in a blood vessel that bulgeoutwards. As they fill with blood and are subjected to continuous cyclicpressure, aneurysms grow and become weaker over time where they couldeventually rupture and lead to internal bleedings. Regenerative stentscan fully shield the aneurysm and take over the load of the artery. Asthe blood flow inside the aneurysm is obstructed, a thrombus can beformed to fill the cavity. Over time a new artery will be created whilethe aneurysm will safely regress as the thrombus is being resorbed. Someembodiments can contain a fibrous network capable to act as aflow-diverting device.

Variations

In some embodiments, markers might be incorporated to enhancetraceability through imaging of the device prior, during or afterimplantation. In some embodiments, contrast agents can be included. Insome embodiments, the device can be further functionalized by includingcell-capturing moieties either on the luminal side, inside the fibrousmesh or on the outside.

In some embodiments, agents like drugs or therapeutics can beincorporated, which can be immune modulative anti-inflammatory (such assteroids), anti-proliferative (such as everolimus), or be agents, whichare therapeutic, prophylactic, or diagnostic. Agents can beantineoplastic, antiplatelet, anti-coagulant, anti-fibrin,antithrombotic, antimitotic, antibiotic, antiallergic, antioxidant,antiinfective, and cystostatic agents.

In some embodiments agents can affect biological processes, comprisingbut not limited to, bioactive agents from entire biological compoundssuch as cytokines, chemokines or other enzymes or peptides thereof fromeither biological or synthetic origin.

In some embodiments, the construct can be used as an agent vehicle.Agents can be incorporated into the fibers by mixing it into the polymersolution prior to conduct production. Agents can be coated on thefibrous surface after conduct production. Agents can be chemicallylinked to the fibrous network. Agents can be chemically linked by makinguse of supramolecular chemistry.

In some embodiments, agents will be released upon implantation. Agentscan be released as the fibers are being absorbed and/or as the coatingon the fibers will absorb over time. Secretion speed of the drugs can becontrolled by tuning the degradation speed of the polymer/coating. Alsochanging the concentration of the included agent will influence therelease profile. When agents are chemically linked, agent can bereleased as the chemical linker is being broken. Breaking the chemicallink can be broken by temperature, pH, ultrasound, additive, orcytokines released by cells. Breaking the chemical links can happenwithout further interference, or can be controlled by specificallyinducing the trigger that initiates chemical link breaking.

In some embodiments, agents can be incorporated into the embodiment toact on: cell infiltration, cell adhesion, tissue formation, tissuecomposition, selective cell recruitment, neointima tissue formation,endothelial cell adhesion, macrophage polarization, cell activation,induce angiogenesis, induce plaque regression in atheroscleroticregions, activate cell contractility, and/or induce tissue degradation.

Fibrous conduits can be positioned in front of a bifurcation or otheropening after implantation, which can hamper passage of biologicalcomponents. To facilitate patency to the obstructed area, the wall ofthe fibrous construct could be adjusted. In some embodiment, a medicaldevice is able to penetrate the wall from the inside to the outside toreach the bifurcation (FIG. 21A). The medical device can be a ballooncatheter that is able to inflate and induce local rearrangement of thefibrous network at the location of the bifurcation (FIG. 21B). Afterremoval of the medical device, the bifurcation remains patent. Inanother embodiment a small hole is created inside the wall of thefibrous network either prior or after implantation. The hole ispositioned in front of the bifurcation and provides patency. This holecan be reshaped by means of similar medical devices such as a ballooncatheter when preferred.

In an exemplarily embodiment, two constructs can be mounted onto aballoon catheter where there is a separation between another (FIG. 21C).After implantation of the stent this separation section can bepositioned in front of the bifurcation to remain patency (FIG. 21A). Inyet another embodiment two constructs can be mounted onto a ballooncatheter where there is a separation between another, and a layer offast absorbable materials can be included to cover the separation. Afterimplantation of the stent the section with the separation covered by afast absorbable material can be positioned in front of the bifurcation,where the fast absorbable layer can remain patency to the bifurcationafter absorption.

The Stent can Contain Additional Embodiments Additional Embodiment 1

The stent can comprise a valve construct. The valve can contain one,two, three or multiple leaflets. The valve can be a mechanical,biological, or synthetic. A synthetic valve can comprise a fibrousnetwork. Biological heart valves can be allografts, autografts orxenografts. The combined stent plus valve embodiment can be used tominimally-invasively replace valve structures such as the heart or inthe veins. The components of an exemplary valved-stent are shown inFIGS. 20A-E. A valved stent can be composed of one or more layers andmight require the use of special mandrels and molds to shape theleaflets, as well as surface treatments and annealing steps.

Addition Embodiment 2

The stent can comprise a cross-sectional membrane. The membrane can bebiological, metallic or synthetic. The membrane can be permeable orimpermeable. The membrane can facilitate or prevent fluid exchange. Themembrane can facilitate or prevent passage of cells or selectivelyfilter them. Filtering can be enabled by tuning the pore size of themembrane. Moieties can be included in the membrane to selectively adhereto cells, enzymes or proteins. The membrane can trigger tissueformation. The combined stent plus membrane embodiment can be used toact as a filter, close ducts or induce an obstruction in a biologicalduct.

The invention claimed is:
 1. A stent for implantation into a biologicalduct, comprising: an expandable tubular construct made out of a fibrousnetwork, wherein the fibrous network distinguishes: (i) a first statewith a first diameter of the tubular construct determined by a firstfiber orientation characterized by a first fiber dispersion and a firstmain angle difference, and a first average fiber diameter, and (ii) asecond state with a second diameter of the tubular construct determinedby a second fiber orientation characterized by a second fiber dispersionand a second main angle difference, and a second average fiber diameter,characterized in that the transition from the first state to the secondstate is accommodated only by rearrangement of the fibers in the fibrousnetwork; and in that the fibrous network in the second state providessupport to the biological duct, with the proviso that the transitiondoes not rely on a strut pattern.
 2. The stent of claim 1, wherein thefirst fiber orientation is an arrangement of random fibers, and whereinthe first fiber dispersion is larger than the second fiber dispersioncontrolled fibers, wherein the first main angle difference is equal orlarger than the second main angle difference; or a combination of saidrandom fibers and controlled fibers.
 3. The stent of claim 1, whereinthe first average fiber diameter is equal to or larger than the secondaverage fiber diameter.
 4. The stent of claim 1, wherein therearrangement of the fibrous network from the first state to the secondstate is accomplished by: stretching and/or straightening of the fibersin the fibrous network; (ii) sliding, breaking, or a combination thereofof the fiber interconnections in the fibrous network; (iii)reorientation and/or realigning of the fibers in the fibrous network; or(iv) a combination of (i), (ii) and/or (iii).
 5. The stent of claim 1,wherein rearrangement of the fibrous network is facilitated by acting onthe wettability of the fibrous network to accommodate the transitionfrom the first state to the second state.
 6. The stent of claim 1,wherein the tubular construct is shaped to induce changes in geometry oropenings.
 7. The stent of claim 1, wherein the tubular construct is madeout of a bio-absorbable fibrous network.
 8. The stent of claim 1,wherein the first diameter of the tubular construct is smaller than thesecond diameter of the tubular construct.
 9. The stent of claim 1,wherein the fibrous network in the second state acts as a scaffold. 10.The stent of claim 1, wherein the fibrous network in the second stateallows for cell infiltration and/or induces autologous tissue formation.11. The stent of claim 1, wherein the fibrous network is composed of oneor more layers of stacked fibers.
 12. The stent according to claim 11,wherein the one or more layers of stacked fibers have differentdensities.
 13. The stent of claim 1, wherein circumferential alignmentof the fibers is promoted by enlargement of the diameter of the tubularconstruct.
 14. The stent of claim 1, wherein the stent comprises a valveconstruct and/or a cross-sectional membrane.
 15. The stent of claim 1,wherein the wall of the fibrous construct is modified by inducing localrearrangement of the fibrous network.
 16. The stent of claim 1, whereinthe rearrangement of the fibers in the fibrous network leads toalignment of the polymer chains in the fibers.